Gonadotropin-releasing hormone type II antagonist induces apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells in vitro and in vivo

Triple-negative breast cancer does not express estrogen and progesterone receptors, and no overexpression/amplification of the HER2-neu gene occurs. Therefore, this subtype of breast cancer lacks the benefits of specific therapies that target these receptors. Today chemotherapy is the only systematic therapy for patients with triple-negative breast cancer. About 50% to 64% of human breast cancers express receptors for gonadotropin-releasing hormone (GnRH), which might be used as a target. New targeted therapies are warranted. Recently, we showed that antagonists of gonadotropin-releasing hormone type II (GnRH-II) induce apoptosis in human endometrial and ovarian cancer cells in vitro and in vivo. This was mediated through activation of stress-induced mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK), followed by activation of proapoptotic protein Bax, loss of mitochondrial membrane potential, and activation of caspase-3. In the present study, we analyzed whether GnRH-II antagonists induce apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells that express GnRH receptors. In addition, we ascertained whether knockdown of GnRH-I receptor expression affects GnRH-II antagonist-induced apoptosis and apoptotic signaling.

A Divided City in a Common Market: EU Citizenship and Everyday Instrumentalities on the Polish-German Border

Based on an ethnographic case study in the border cities of Frankfurt (Oder), Germany and Słubice, Poland, this article explores the construction and maintenance of ethnic difference within the transnational economic and social spaces created by the European Union's common market. Through an examination of three domains of cross-border citizenship practice - shopping and consumption, housing and work - this article argues that even as the European Union deploys policies aimed at creating de-territorialised and supranational forms of identity and citizenship, economic asymmetries and hierarchies of value embedded within these policies grant rights differentially in ways that continue to be linked to ethnicity and nationality.

Molecular Dynamics Simulation of a PNA·DNA·PNA Triple Helix in Aqueous Solution

Molecular dynamics simulations have been used to explore the conformational flexibility of a PNA·DNA·PNA triple helix in aqueous solution. Three 1.05 ns trajectories starting from different but reasonable conformations have been generated and analyzed in detail. All three trajectories converge within about 300 ps to produce stable and very similar conformational ensembles, which resemble the crystal structure conformation in many details. However, in contrast to the crystal structure, there is a tendency for the direct hydrogen-bonds observed between the amide hydrogens of the Hoogsteen-binding PNA strand and the phosphate oxygens of the DNA strand to be replaced by water-mediated hydrogen bonds, which also involve pyrimidine O2 atoms. This structural transition does not appear to weaken the triplex structure but alters groove widths and so may relate to the potential for recognition of such structures by other ligands (small molecules or proteins). Energetic analysis leads us to conclude that the reason that the hybrid PNA/DNA triplex has quite different helical characteristics from the all-DNA triplex is not because the additional flexibility imparted by the replacement of sugar−phosphate by PNA backbones allows motions to improve base-stacking but rather that base-stacking interactions are very similar in both types of triplex and the driving force comes from weak but definate conformational preferences of the PNA strands.

Molecular Dynamics Simulations of the d(TAT) Triple Helix

Molecular dynamics (MD) simulations have been used to study the dynamical and time-averaged characteristics of the DNA triple helix d(T)10âd(A)10âd(T)10. The structures sampled during the trajectory resemble closely the B-type model for the DNA triplex proposed on the basis of NMR data, although there are some subtle differences. Alternative P- and A-type conformations for the triplex, suggested from X-ray experiments, are not predicted to contribute significantly to the structure of the DNA triplex in solution. Comparison with the best available experimental data supports the correctnes of the MD-generated structures. The analysis of the collected data gives a detailed picture of the characteristics of triple-helix DNA. A new and interesting pattern of hydration, specific for triplex DNA, is an important observation. The results suggest that molecular dynamics can be useful for the study of novel nucleic acid structures.

Decompression during Late Proterozoic Al2SiO5 Triple-Point Metamorphism at Cerro Colorado, New Mexico

An outstanding problem in understanding the late Proterozoic tectonic assembly of the southwest is identifying the tectonic setting associated with regional metamorphism at 1.4 Ga. Both isobaric heating and cooling, and counter-clockwise looping PT paths are proposed for this time. We present a study of the Proterozoic metamorphic and deformation history of the Cerro Colorado area, southern Tusas Mountains, New Mexico, which shows that the metamorphism in this area records near-isothermal decompression from 6 to 4 kbar at ca. 1.4 Ga. We do not see evidence for isobaric heating at this time. Decompression from peak pressures is recorded by the reaction Ms + Grt = St + Bt, with a negative slope in PT space; the reaction Ms + Grt = Sil + Bt, which is nearly horizontal in PT space; and partial to total pseudomorphing of kyanite by sillimanite during the main phase of deformation. The clearest reaction texture indicating decompression near peak metamorphic temperature is the replacement of garnet by clots of sillimanite, which are surrounded by halos of biotite. The sillimanite clots, most without relict garnet in the cores and with highly variable aspect ratios, are aligned. They define a lineation that formed with the dominant foliation. An inverted metamorphic gradient is locally defined by sillimanite-garnet schists (625 degrees C) structurally above staurolite-garnet schists (550 degrees C) and implies ductile thrusting during the main phase of deformation. The exhumation that led to the recorded decompression was likely in response to crustal thickening due to ductile thrusting and subsequent denudation.

Narrating Boundaries: Framing and Contesting Suffering, Community, and Belonging in Enclaves along the India-Bangladesh Border

This paper explores the politics of community making at the India-Bangladesh border by examining the public and private narratives of history and belonging in a Bangladeshi enclave-a sovereign piece of Bangladesh completely territorially surrounded by India. Drawing on framings of political society, this paper argues that understanding populations at the margins of South Asia and beyond requires attention to two processes: first, to the ways that para-legal activities are part and parcel of daily life; and second, to the strategies through which these groups construct themselves as moral communities deserving of inclusion within the state. Border communities often articulate narratives of dispossession, exceptionality, and marginalization to researchers and other visitors-narratives that are often unproblematically reproduced in academic treatments of the border. However, such articulations mask both the complicated histories and quotidian realities of border life. This paper views these articulations as political projects in and of themselves. By reading the more hidden histories of life in this border enclave, this article reconstructs the notion of borders as experienced by enclave residents themselves. It shows the ways that the politics of the India-Bangladesh border are constitutive of (and constituted by) a range of fractures and internal boundaries within the enclave. These boundaries are as central to forging community-to articulating who belongs and why-as are more public narratives that frame enclave residents as victims of confused territorial configurations. (C) 2012 Elsevier Ltd. All rights reserved.

Polymorphisms in the ABCB1 gene in phenobarbital responsive and resistant idiopathic epileptic Border Collies

BACKGROUND: Variation in the ABCB1 gene is believed to play a role in drug resistance in epilepsy. HYPOTHESIS/OBJECTIVES: Variation in the ABCB1 gene encoding the permeability-glycoprotein could have an influence on phenobarbital (PB) resistance, which occurs with high frequency in idiopathic epileptic Border Collies (BCs). Animals: Two hundred and thirty-six client-owned BCs from Switzerland and Germany including 25 with idiopathic epilepsy, of which 13 were resistant to PB treatment. METHODS: Prospective and retrospective case-control study. Data were collected retrospectively regarding disease status, antiepileptic drug (AED) therapy, and drug responsiveness. The frequency of a known mutation in the ABCB1 gene (4 base-pair deletion in the ABCB1 gene [c.296_299del]) was determined in all BCs. Additionally, the ABCB1 coding exons and flanking sequences were completely sequenced to search for additional variation in 41 BCs. Association analyses were performed in 2 case-control studies: idiopathic epileptic and control BCs and PB-responsive and resistant idiopathic epileptic BCs. RESULTS: One of 236 BCs (0.4%) was heterozygous for the mutation in the ABCB1 gene (c.296_299del). A total of 23 variations were identified in the ABCB1 gene: 4 in exons and 19 in introns. The G-allele of the c.-6-180T > G variation in intron 1 was significantly more frequent in epileptic BCs resistant to PB treatment than in epileptic BCs responsive to PB treatment (P(raw) = .0025). CONCLUSIONS AND CLINICAL IMPORTANCE: A variation in intron 1 of the ABCB1 gene is associated with drug responsiveness in BCs. This might indicate that regulatory mutations affecting the expression level of ABCB1 could exist, which may influence the reaction of a dog to AEDs.

Triple innominate osteotomy for Legg-Calvé-Perthes disease in children: does the lateral coverage change with time?

Triple innominate osteotomy (TIO) is one of the modalities of surgical containment in Legg-Calvé-Perthes disease (LCPD). However, overcoverage with TIO can lead to pincer impingement.